The initation and maintenance of chronic pulmonary inflammation are dependent upon dynamic interactions between an inciting agent, inflammatory mediators, leukocytes, and structural cells of the lung. Independent of the etiology these interactions set in motion a chronic cascade of events, which contribute to the pathology of granulomatous lung disease, including altered lung physiology, intense inflammation, and an impaired healing response leading to fibrosis. Our over-arching general theme of this section is to determine how the expression and regulation of specific chemokines and their receptors support the initiation and maintenance of experimental lung granulomas characterized by defined cytokine phenotypes. Specifically, we will investigate the mechanisms whereby CCR4 and its IigandsTARC/CCL17 (Thymus and activated chemokine) and MDC/CCL22 (monocyte-derived chemoattractant) contribute to the pathology of chronic lung inflammation. Our data support the concept that CCR4 and it ligands are differentially expressed during the evolution of granulomatous lung inflammation and they possesses novel biological activities associated with granuloma development and fibrosis. Based on these data, we hypothesize that TARC/MDC:CCR4 expression, by both structural cells and leukocytes, are key components of chronic lung inflammation via their ability to modulate cytokine expression, fibroblast activity and leukocyte activation and elicitation. Our studies will focus on the following Specific Aims: To investigate the time-course, magnitude of expression, cellular sources, and mechanisms of expression of CCR4, TARC, and MDC during the evolution of chronic lung inflammation characterized by a type 1 or type 2 cytokine profile. To determine the mechanistic role by which TARC, MDC, and CCR4 expression can regulate the progression of chronic lung inflammation by influencing cytokine expression profiles, fibroblast activation, and leukocyte activation and elicitation. To assess the contribution of resident, structural cell-derived CCR4 and TARC to the maintenance of chronic lung inflammation, via -/- mice and immunoneutralization. To investigate the mechanism of TARC/MDC-CCR4-dependent fibroblast-leukocyte interactions, as an important mechanism for the maintenance of chronic inflammation. We will study well characterized models of chronic lung inflammation in normal and knockout mice using immuno-neutralization, bioassays, ELISAs, Taq-Man RT-PCR, and array analyses. The studies designed in this proposal will show that CCR4 and its ligands play novel roles in the maintenance of chronic lung inflammation and will serve as excellent targets for therapeutic interventions.